O-Quinone methide intermediates

From the synthetic investigations that have been described in the previous schemes, an appreciation of the mechanism for these reactions (methods A-H) has emerged in our group. However, the characteristics and exact nature of the o-quinone methide intermediate are still debated. Our past observations clearly indicate the cascade leading to the reactive species that behaves as an o-quinone methide should behave is... 

Van De Water, R. W. Pettus, T. R. R. o-Quinone methides intermediates underdeveloped and underutilized in organic chemistry. Tetrahedron 2002, 58, 5367-5405. 

Substituted 2-aminonaphthalenes have been prepared on Wang resin by cyclocondensation of resin-bound 2-trifluoromethylphenyl acetate with arylacetonitriles (Figure 10.7). This reaction probably proceeds via an electrophilic o-quinone methide intermediate, formed by base-induced elimination of HF from the resin-bound ester [229]. 

Intramolecular phenol alkylation. Phenols of type 1,3, and 4 when treated with ethylmagnesium bromide in benzene at reflux undergo intramolecular alkylation. These reactions are thought to proceed via o-quinone methide intermediates such as b formulated for the case of 1. These cyclizations fail with NaH or n -butyllithium as... 

An example of this overall approach in elucidating novel bioactivation pathways is highlighted with studies on the potassium channel opener, maxipost (BMS-204352) (Figure 6.2), which undergoes a unique P450-mediated bioactivation reaction in rats, dogs, and humans to yield an electrophilic o-quinone-methide intermediate, which covalently binds to albumin in vivo in animals and human.33-34 Acidic hydrolysis of plasma collected after intravenous administration of [14C]-BMS-204352 to rats and human led to the characterization of a... 

Lower reaction temperatures favor the reversible formation of the Diels-Alder products, and higher reaction temperatures promote the irreversible ene reactions. Related observations of the competing or predominating intramolecular Diels-Alder reactions of a-cyano or a-acetyl a,/3-unsaturated esters have been reported in studies of the thermal and Lewis acid-promoted ene reaction (Table 7-II, entry 16).143 The complementary use of o-quinone methide intermediates in intra- as well as inter-molecular [4 + 2] cycloaddition reactions is discussed in the following section. 

The reaction of chlorotrimethylsilane with hydroxymethylspiroepoxycy-clohexadienone (20) affords the spiroannelated chroman 21. The reaction presumably proceeds through an o-quinone methide intermediate which dimerizes to the chroman [Eq. (42)].167... 

Scheme 7.64 Synthesis of 2 -aminobenzothiazolo-(4-methylphenyl)methyl-4-nitrophenol and 2 -aminobenzothiazolomethyl-2-naphthols via o-quinone methide intermediate.

A novel and efficient method for the generation of o-quinone methide intermediates under mild basic conditions, from readily available 2-tosylalkylphenols, has been developed and their reactions with sulfur ylides have been investigated for the stereoselective synthesis of tra i -2,3-dihydrobenzofurans (<98% de) ... 

Recently, the synthetic utility of dimethyl formamide (DMF) as the nucleophilic trigger in aryne MCRs was developed independently by the Miyabe and Yoshida groups. The three-component coupling reaction between aryne, DMF, and an active methylene compound such as acetyl acetone, dibenzoyl methane, cyclohexane 1,3-dione, etc. resulted in the formation of either 2H-chromenes 105 or coumarin derivatives 106 [75,76]. The insertion of fhe carbonyl group of DMF to the aryne generates the o-quinone methide intermediate 104. Subsequent reaction of 104 with cyclic or acyclic 1,3-diketones as the third component resulted in the formation of 2H-chromenes 105. Intriguingly, furnished coumarin derivatives 106 were formed when 3-ketoester or a-(hetero)aryl esters were used as the third component (Scheme 53). 

Intermolecular hydroalkoxylation of vinylphenols has been developed by Sigman using Pd(II) and primary, secondary or tertiary alcohols. The key breakthrough was the use of sec-phenetyl alcohol as the sacrificial reagent as the hydride source promoting the formation of Pd-H intermediate. The subsequent olefin insertion, the formation of an o-quinone methide intermediate and the addition of... 

Uchida and Irie have reported a photochromic system based on ESIPT to an alkene carbon.82 They observed that vinylnaphthol 121 isomerizes to the ring-closed 123 when irradiated with 334 nm light ( = 0.20, Eq. 1.34). The reaction is photoreversible since irradiation of 123 (at400 nm) regenerates the starting vinylnaphthol. The authors proposed a mechanism in which ESIPT from the naphthol OH to the [3-alkenyl carbon gives intermediate o-quinone methide 122, which undergoes subsequent electrocyclic... 

The prototype o-quinone methide (o-QM) and / -quinone methide (p-QM) are reactive intermediates. In fact, they have only been detected spectroscopically at low temperatures (10 K) in an argon matrix,1 or as a transient species by laser flash photolysis.2 Such a reactivity is mainly due to their electrophilic nature, which is remarkable in comparison to that of other neutral electrophiles. In fact, QMs are excellent Michael acceptors, and nucleophiles add very fast under mild conditions at the QM exocyclic methylene group to form benzylic adducts, according to Scheme 2.1.2a 3... 

Amouri and coworkers also demonstrated that the nucleophilic reactivity of the exocyclic carbon of Cp Ir(T 4-QM) complex 24 could be utilized to form carbon -carbon bonds with electron-poor alkenes and alkynes serving as electrophiles or cycloaddition partners (Scheme 3.17).29 For example, when complex 24 was treated with the electron-poor methyl propynoate, a new o-quinone methide complex 28 was formed. The authors suggest that the reaction could be initiated by nucleophilic attack of the terminal carbon of the exocyclic methylene group on the terminal carbon of the alkyne, generating a zwitterionic oxo-dienyl intermediate, followed by proton transfer... 

The groups of Liebeskind and Moore independently explored the ring expansion of allenyl-substituted cyclobutenol derivatives. This allows either the preparation of 5-alkylidene-2-cyclopentenones, which are substructures of naturally occurring bioactive compounds [59], or the generation of o-quinone methides, which are very attractive intermediates in the synthesis of hexahydrocannabinols [109]. As shown in Scheme 8.42, the ring expansion of the tetrasubstituted methoxyallene derivative 170 furnished the vinylhydroquinone 172 in high yield [109]. 

Based on the evidence obtained from the amount and nature of transformation products formed, a mechanism of melt stabilising action of tocopherol in PP and PE has been proposed, see Scheme 6 [34]. It is well known that, like other hindered phenols, a-tocopherol is rapidly oxidised by alkylperoxyl radicals to the corresponding tocopheroxyl radical (a-Toe, Scheme 6a). Further oxidation of the tocopheroxyl radical in the polymers leads to the formation of coupled and quinonoid-type products, e.g. SPD, TRI, DHD (see Figs. 8 and 9). Dimerisation of the intermediate o-quinone methide (QM) leads to the formation of the quinonoid-type dimeric coupled product, SPD (Scheme 6 reaction d). 

Bispyrano-l,4-benzoquinones 18 are readily formed regioselectively but as separable diastereomers when a mixture of 2,5-dihydroxy-l,4-benzoquinone, paraformaldehyde and an electron-rich alkene is heated under microwave irradiation. A double domino Knoevenagel -HDA is involved with generation of an o-quinone methide type of intermediate <07T3066>. 

Synthesis o/eslra-l,3,5(10)-(rieiie-17-oii . Nicolaou and Barnette report that sultone 1 is metalated with KH in DME to afford a clear yellow solution of the anion 2. Alkylation of 2 with tosylate 3 followed by acid hydrolysis affords 4 as a mixture of diastereomers in 77% yield. Thermolysis of 4 affords estra-1,3,5(10)-triene-17-one (5) directly in 85% yield, probably by way of an intermediate o-quinone methide a. This sequence constitutes an exceedingly short and efficient synthesis of the steroid nucleus. 

Dihydrobenzoxanthenes 27 result from the photolysis of 2-(l-naphthyl)phenols a quinone methide intermediate is postulated. The twisted nature of the o-hydroxybiaryl system facilitates excited-state intramolecular proton transfer (ESIPT) at both the 2 - and 7 -positions <03JA1164>,... 

Saegusa s group (81JA5250) found that [o-[(trimethylsilyl)alkylamino]-benzyljtrimethylammonium halide underwent the fluoride-anion induced 1,4-elimination under mild conditions to generate an o-quinone methide N-alkylamine intermediate. They performed the formal synthesis of gephyro-toxin 434 on the basis of an intramolecular cycloaddition of the o-quinone methide A-alkylamine 426 (83TL2881). Treatment of azadiene precursor 425... 

Fluoride-induced fragmentation reactions were used in two stages of a synthesis of hexahydrocannabi-nol methyl ether (144 Scheme 52). One of the phenolic hydroxy functions in the resorcinol derivative (140) was selectively liberated from the SEM ether to give the diol (141), which was converted to the bis (trimethylsilyl) ether (142). Subsequent treatment with CsF resulted in a 1,4-elimination to the o-quinone methide (143) intermediate, which underwent an intramolecular [4 -i- 2] cycloaddition to give the product in good yield. 

---